Series of nitrofuran compounds comprising the azomethines of 5-nitro-2-acyl furans with 1-amino-hydantoins



Patented Sept. 9, 1952 scams F NITROFURAN COMPOUNDS coil.

rmsme THE AZOMETHINES or s-m'rao- ,Z-ACYL FURANS wrrn I-AMINO-HYDAN- TOINS Kenyon J. Hayes, Norwich, N. Y., assignor to Eaton Laboratories, Inc., Norwich, N. Y., a corporation of New York No Drawing. Application May 29, 1950,

r Serial No. 165,095,

X H II o2N C=N-N NR o l 1 i RCH- =0 in which:

X represents 0 or S R represents hydrogen or lower alkyl (C1-C'4) R. represents hydrogen or lower alkyl (Ci-Cs) R" represents hydrogen or lower alkyl (Ci-C's) and in which:

R+R contain not more than 6 carbon atoms,

and

R+R+R" contain not more than 6 carbon atoms.

I have discovered that the exceptional resistance to breakdown by the bodily processes shown by members of this series allows excretion in the urine of dosed animals which is highly antibacterial. This, in conjunction with chemotherapeutically effective blood levels, makes these members especially useful in the treatment of many urinary tract infections. Chemotherapeutic effects are attainable at less than toxic doses. These members are very effective antibacterial agents against Staph. aureus and Strep. hema, as well as against E, coli, S. jaecalis and P. culgarz's, which are of particular concern in many urinary tract infections.

The various members of this new series of drugs differ from each other somewhat in degree of chemotherapeutic effectiveness; This is due, in part, to resultant differences in physical properties such as water solubility and oil/water distribution ratios.

Of the series, I now prefer a particular member, N nitro-z-furfurylidene) -1-amino-hydantoin. This is a relatively stable, yellow solid, which is readily prepared by well-known reactions.

In general the l-amino-hydantoins are prepared by condensation of a-hydrazino-aliphatic carboxylic acids or their esters with cyanic acid, thiocyanic acid or alkyl isocyanates or alkyl mus- 6 Claims. (Cl. 260-240) tard oils, followed by cyclization of the resultant u-(Z-semicarbaZidO) -aliphatic carboxylic acids or esters, which may be effected by heat with or without acid as catalyst. The l-amino-hydantoins thus obtained may be isolated or condensed directly with 5-nitro-2-furaldehyde, 5-nitro-2- furyl methyl ketone etc. in neutral or moderately acid media. The 5-nitro-2-furaldehyde may also be generated directly in an acid meida containing the l-amino-hydantoin as by hydrolysis of 5- nitro-2-furaldehyde diacetate.

In order that this invention may be fully disclosed to those skilled in the art, methods for preparing a number of these new compounds are described briefly: 1

Elm MPLE 1 p N (5 -nitro-2-furjurylidene) -1 -amino-hydamtoin A solution of approximately 0.5 gram mole 1- amino-hydantoin sulfate in an aqueous solution (7 liters) containing approximately 8% acetic acid and containing approximately 12% sulfuric acid was prepared essentially by the method of Traube and Hoffa (Ber. 31, 167 (1898)).

To this was added a ten percent molal excess of 5-nitro-2-furaldehyde diacetate and about 10 volume percent of ethanol. The mixture was stirred and heated at approximately C. for one-half hour, then cooled to 10 C, to yield orange-yellow needles of N -(5- nitro-2-furfurylidene)-1-amino-hydantoin. The material was well washed with water and alcohol. This material melts with decomposition at 251-253 C. uncorr. An aqeuous solution absorbs in the ultraviolet at 3700 A.

EXAMPLE 2 N (5 -nitro-2-furfurylidene) -1 -amino-5-methylhydantoin 0o O'zN JCH=N-N/ \NH CH: H oo 1-amino-5-methylhydantoin sulfate was prepared by the method of Bailey and Mikeska (J. A. C. S. 38," 1782 (1916) To 2.13 gms. in cc. of 1:1 ethanol-water was added 4.5 gins. of 5-nitroz-furaldehyde. After heating and stirring for N 5 nritro-ZJurylacetylidene) -1 -am'm o- 5 -methylhydantoin H CH3 CHsCHeCO 1-amino-5-methylhydantoin sulfate, prepared by the method of Bailey and Mikeska (J. A.- C.

S. 38, 1782 (1916)), was dissolved in Water, bufe EXAMPLE 4 N- (5-=nitro-2-furfurylidene) -1 -amino- Z-thz'ohydantoin To an efficiently agitated suspension of 20 gms. of ethyl hydrazinoacetate hydrochloride in 140 cc. of glacial acetic acid are added 19.3 gms. .3

of potassium thiocyanate in small portions over a period of two hours at a temperature of 27 C. After this addition period the reaction mixture is stirred at 28 C. for 3 hours and then filtered to remove insoluble salts. The clear filtrate is concentrated to a pasty mass by distillation under a pressure of 20 mm. Hg. Finally the residue is heated for 12 minutes at 120 C. under vacuum. 9.34 gins. of crude ethyl-2-thiosemicarbazidoacetate of M. P. 121-127 C. can be isolated by recrystallizin this material from 50 cc. of water.

8 gins. of the thiosernicarbazido intermediate are then refluxed with 100 cc. of water for hours. Crude l-amino-Z-thiohydantoin precipitates on cooling the solution; recrystallization from ethanol yields 2.4 gins. of the thiohydantoin which melts completely at about 191 C.

The addition of 2.7 gins. of -nitro-2-furaldehyde to 2.4 gms. of the thiohydantoin compound in 200 cc. of hot ethanol yields approximately 4.4

gms. of N-(5-nitro-2-furfuryiidene) -1-amino-2- thiohydantoin. The pure nitrofuran melts with final decomposition at 225 C.

EXAMPLE 5 N 5-m'tro-2-furfurylid'ene) -1 -ami'rio-3- methyZ-Z-thiohydantoin CHr-C 0 4. EXAMPLE 6 N (5 nitro 2 furfm'ylide'ne) -1-ami-no-5-nbutylhydantoin V -CHa(CH2)aCH-(LO v ,Toawell. stirred suspension of 13 grams of benzylidenehydrazino caproic acid, prepared by the method of- H. Berger (J. prak. Chem. 152, 309 (1939) Min- 217 cc. of glacial acetic acid are added 5.7"grams of potassium cyanate, in small an o r.-

portionsyduring the course of three-quarters of The. temperature is maintained at 20-30 C. during the addition and for approxi- "mately three hours thereafter. Treatment with 60 cc. of benzene and 1200 cc. of water causes the precipitation of slightly impure benzylidene-2- semicarbazidocaproic acid of M. P. ISO-165 0., yield 8.4 grams.

Eight grams of the crude benZylideneFZ-Semicarbazidocaproic acid are suspended in cc. of water containing 14 cc. of concentrated sulfuric acid and subjected to steam-distillation to remove the benzaldehyde and to cyclize the semicarbazido acid to the l-amino-hydantoin derivative. The resulting solution is clarified, and the volume adjusted to 340 cc. by the addition of water. A solution of 3.74 grams of 5-nitro-2-furaldehyde in 8 cc. of ethanol is then added and the resulting mixture is stirred about one-half hour at room temperature to complete the reaction. The yellow product is filtered, washed and dried. Yield 5.7 grams; M. P. 175.5-176.5 C. i

What is claimed is:

1. A compound having chemotherapeutic activity and resistance to metabolic destruction and represented by the formula:

X represents a member of the group consisting of O' and S 15. represents a member of the group consisting of hydrogen and a lower alkyl radical containing from 1 to 4 carbon atoms R represents a member of the group consisting of hydrogen and a lower alkyl radical containing from 1 to 6 carbon atoms R" represents a member of the-group consisting of hydrogen and a lower alkyl radical containing from 1 to 6 carbon atoms and in which:

R-l-R." contain not morethan 6 carbon. atoms,

and

R+R,+R contain not more than 6 carbon atoms. 1

2. N (5 -,nitro 2 furfurylidene)-1,-aminohydantoin represented by the. formula:

OgN CH=NN N o 1 1 ciao-00 3. N-(5-nitro-2-furfurylidene) 1 amino 5- metliyl-hydantoin represented by the formula:

I CH3 0,0.

5 6 4. N-(5-nitro-2-furylacetylidene) 1 amino- 6. N-(5-mtro-2-turfurylidene) 1 amino -3 S-methylhydantoin represented by the formula: methyl-Z-thiohydantoin represented by the formula:

00 ON C=NN/ \NH 5 0s O (17H: N O 0, O/CH-N-N NCH: 5. N-(5-nitro-2-furfury1idene) 1 amino 2- CH? 0 thiohydantoin represented by the formula:

10 KENYON J. HAYES.

0s ON 0 No references cited. 

1. A COMPOUND HAVING CHEMOTHERAPEUTIC ACTIVITY AND RESISTANCE TO METABOLIC DESTRUCTION AND REPRESENTED BY THE FORMULA: 